Synthesis and studies on the mGluR agonist activity of FAP4 stereoisomers.

The four stereoisomers of 1-amino-2-fluoro-2-(phosphonomethyl)cyclopropane-1-carboxylic acid (FAP4) were synthesized via diastereoselective Rh(II)-catalysed cyclopropanation of a phosphonylated fluoroalkene. Different isomers of FAP4 and the corresponding non-fluorinated analogs showed a similar pharmacological profile against the isoforms of metabotropic glutamate receptor (mGluR). Within the fluorinated series, (-)-(Z)-FAP4 and (-)-(E)-FAP4 demonstrated the highest agonist activity against mGlu4 (EC50 0.10 µM). Our results suggest that fluorocyclopropanes bearing an amino-acid function can be suitable for the development of potent conformationally restricted mGluR agonists.

[(18) F]CuCF3 : a [(18) F]trifluoromethylating agent for arylboronic acids and aryl iodides.

Positron emission tomography has emerged as the leading method for medical imaging with fluorine-18 as the most widely used radioactive isotope. Here we report a semi-automated method for the preparation of valuable [(18) F]trifluoromethylcopper, as well as its use for the radiosynthesis of [(18) F]trifluoromethylarenes and heteroarenes. Mild conditions of [(18) F]trifluoromethylation make this method particularly useful for the radiosynthesis of pharmacologically relevant [(18) F]trifluoromethylarenes and heteroarenes.

Indium-promoted diastereoselective addition of fluorinated haloallylic derivatives to imines.

We report herein the first general access to fluorinated homoallylic amines by means of an addition of fluorinated organoindium reagent. The corresponding amines were obtained in good to excellent yield with excellent diastereoisomeric ratio. A plausible mechanism is proposed to explain the stereochemical outcome of the reaction based on the X-ray structure of the products.

Grob fragmentation of 2-azabicyclo[2.2.2]oct-7-ene: tool for the stereoselective synthesis of polysubstituted piperidines.

The Grob fragmentation of azabicyclo[2.2.2]octene leads to a dihydropyridinium intermediate. This highly reactive species reacts with a variety of organocuprates and other soft nucleophiles in a regioselective manner, allowing for the rapid and stereoselective synthesis of 2,3,4-trisubstituted 1,2,3,4-tetrahydropyridines. The resulting products were either reduced in situ to the corresponding piperidine or used to achieve the stereoselective construction of various nitrogen heterocycles.

Α-amino-ß-fluorocyclopropanecarboxylic acids as a new tool for drug development: synthesis of glutamic acid analogs and agonist activity towards metabotropic glutamate receptor 4.

Herein we describe the diastereoselective synthesis of glutamic acid analogs and the evaluation of their agonist activity towards metabotropic glutamate receptor subtype 4 (mGluR4). These analogs are based on a monofluorinated cyclopropane core substituted with an α-aminoacid function. The potential of this new building block as a tool for the development of a novel class of drugs is demonstrated with racemic analog 11a that displayed the best agonist activity with an EC50 of 340 nM.

Stereoselective synthesis of 2,3,6-trisubstituted tetrahydropyridines via Tf(2)O-mediated Grob fragmentation: access to indolizidines (-)-209I and (-)-223J.

Herein we describe the γ-amino hydroxide Grob fragmentation of the aza-bicyclo[2.2.2]octene 1 using triflic anhydride as the activating agent. The resulting dihydropyridinium ion can react with a wide variety of Grignard reagents, giving access to 2,3,6-trisubstituted tetrahydropyridines (2) with high regio- and stereoselectivities. This methodology has been applied to the short synthesis of natural indolizidines (-)-209I (3) and (-)-223J (4).

Rhodium-catalyzed cyclopropanation of fluorinated olefins: a straightforward route to highly functionalized fluorocyclopropanes.

An efficient access to highly functionalized monofluorocyclopropanes is described. The developed methodology allowed straightforward access to a large panel of polysubstituted fluorinated cyclopropanes in good to excellent yields and good diastereoselectivities. The Rh-catalyzed cyclopropanation proved to be efficient on several fluorinated olefins and several diazo compounds. This method represents the first general route to complex fluorinated cyclopropanes.

Toward the Synthesis of Fluorinated Analogues of HCV NS3/4A Serine Protease Inhibitors Using Methyl α-Amino-ß-fluoro-ß-vinylcyclopropanecarboxylate as Key Intermediate.

Synthesis of fluorocyclopropyl building blocks, which constitute the core of various therapeutic agents against the hepatitis C virus, is described. The relevant methyl α-amino-ß-fluoro-ß-vinylcyclopropanecarboxylate has been used as a key intermediate for the total synthesis of a fluorinated analogue of Simeprevir (TMC 435), a HCV NS3/4A protease inhibitor.

First efficient synthesis of fluorinated glycidic esters from ketones.

Treatment of various ketones with ethyl dibromofluoroacetate in the presence of diethylzinc and dimethylaminoethanol or triphenylphosphine provides rapid access to corresponding fluorinated glycidic esters. Simplified workup allowed first characterization of these compounds.